| Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies. | |
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MedLine Citation:
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PMID: 19398345 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6-8) of some acidic NSAIDs (1-3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6-8) were confirmed by IR, (1)H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6-8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t(1/2) approximately 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6-8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4days. In addition, docking of the mutual ester prodrugs (6-8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site. |
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Authors:
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Ahmed Z Abdel-Azeem; Atef A Abdel-Hafez; Gamal S El-Karamany; Hassan H Farag |
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Publication Detail:
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Type: Journal Article Date: 2009-04-08 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry Volume: 17 ISSN: 1464-3391 ISO Abbreviation: Bioorg. Med. Chem. Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-05-06 Completed Date: 2009-06-30 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9413298 Medline TA: Bioorg Med Chem Country: England |
Other Details:
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Languages: eng Pagination: 3665-70 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Animals Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis, chemistry, pharmacology* Carboxylic Acids / chemical synthesis, chemistry* Catalytic Domain Chlorzoxazone / analogs & derivatives*, chemical synthesis, chemistry, pharmacology* Computer Simulation Cyclooxygenase 2 / chemistry, metabolism Drug Design Drug Stability Esters / chemical synthesis, chemistry, pharmacology Male Prodrugs / chemical synthesis, chemistry, pharmacology* Rats Rats, Wistar Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents, Non-Steroidal; 0/Carboxylic Acids; 0/Esters; 0/Prodrugs; 95-25-0/Chlorzoxazone; EC 1.14.99.1/Cyclooxygenase 2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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